Terephthalamide derivatives as mimetics of helical peptides: disruption of the Bcl-x(L)/Bak interaction

A series of Bcl-x(L)/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the alpha-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-x(L)/Bak BH3 domain complex (terephthalamides 9 and 26, K(i) = 0.78 +/- 0.07 and 1.85 +/- 0.32 microM, respectively). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-x(L)/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-x(L)/Bax interaction in whole cells with an IC(50) of 35.0 microM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x(L) is the target area for these synthetic inhibitors.     

Impact of Geometric Parameters,Charge, and Lipophilicity on Bioactivity of Armed Quinoxaline,Benzothiaole, and Benzothiazine: Pom Analyses of Antibacterial and Antifungal Activity

Abstract

A series of four different armed heterocyclic candidates; 1-(2-methyl-2,3-dihydro-1,3-benzothiazol-2-yl)acetone (2), 1-(3-methyl-4H-1,4-benzothiazin-2-yl)ethanone (3), 2-[(2-aminophenyl)dithio]aniline (4), and 3-hydroxy-3-methyl-4-(3-methyl-2-quinoxalinyl)-2-butanone (5) have been prepared and their microbial activities were evaluated. A correlation of the structure and activities relationships of these compounds with respect to molecular modeling, Lipinski Rule of Five, drug likeness, toxicity profiles, and other physico-chemical properties of drugs are described and verified experimentally.     

Structure of 2-[(Phenyl)-(3,5-Dimethyl-Pyrazol-1-yl)-Methyl]-Malonic Acid Diethyl Ester

Abstract  

The titled new functionalized ligand of type 2-[(phenyl)-(3,5-dimethyl-pyrazol-1-yl)-methyl]-malonic acid diethyl ester (4) is prepared in good yield through condensation of 3,5-dimethyl-pyrazole, with 2-arylidene-malonic acid diethyl esters 3. The structure of 4 was determined by spectral (IR, ¹H and ¹³C NMR), elemental analyses and X-ray diffraction data. The title compound (4) crystallizes in the monoclinic space group P2₁/a, with a = 7.9253 (2), b = 17.1299 (5), c = 13.4522 (4) ?, β = 90.220 (2)°, V = 1,826.25 (9) ?³, Z = 4 and with R _int = 0.021. The molecular conformation shows two possible pockets ready to coordinate two metal atoms. The crystal structure of (4) is stabilized by inter-molecular C–H⋯O and C–H⋯N hydrogen bonding.     

Nonlinear fractional differential equations of Sobolev type

Sobolev type nonlinear equations with time fractional derivatives are considered. Using the test function method, limiting exponents for nonexistence of solutions are found. Copyright © 2013 John Wiley & Sons, Ltd.     

Solidification of nano-enhanced phase change material (NEPCM) in a wavy cavity

The effects of surface waviness (λ?=?0, 0.125, 0.25, 0.5) and nanoparticle dispersion (??=?0, 0.05, 0.1) on solidification of Cu-water nanofluid inside a vertical enclosure are investigated numerically for different Grashof number (Gr?=?10⁵, 10⁶, 10⁷). An enthalpy porosity technique is used to trace the solid and liquid interface. Comparisons with previously published works show the accuracy of the obtained results. A maximum of 25.9% relative variation of freezing time with surface waviness was observed for λ?=?0.5, while the relative variation of freezing time with nanoparticles in comparison with surface waviness was negative for high values of λ. It was observed that surface waviness can be used to control the solidification time based on enhancing different mechanism of solidification.     

On a recent result of Cazenave,Dickstein and Weissler

In this note, we present an estimate from below of the blow-up time of blowing-up solutions of a non-linear non-local in the time evolution equation recently introduced by Cazenave et al. (2008) [1]. Moreover, we give an alternative proof of one of the results of Cazenave et al. (2008) [1] which gives more precise information on the hypotheses than those in the paper Cazenave et al. (2008) [1].     

Reaction des acyloxy-2 chloro-3 chloromethyl-2 propanamides avec l'hydroxyde de potassium ou le fluorure de cesium en milieu heterogene synthese de spiro β-lactames

The reaction of cesium fluoride with the 2-acyloxy 3-chloro 2-chloromethylpropanamides ($\text{4}$) gave the 3-acyloxy 3-chloromethyl azetidine 2-ones ($\text{6}$) . Treated by powdered potassium hydroxide, $\text{4}$ and $\text{6}$ were converted into the 1-oxa 4-oxo 5-aza spiro (2,3) hexanes. These reactions in heterogeneous media were very selective and gave excellent yields.     

Synthesis of 9-Arylhexahydroacridine-1,8-diones Using Phosphate Fertilizers as Heterogeneous Catalysts

Russian Journal of Organic Chemistry - A new strategy has been proposed for the synthesis of 9-arylhexahydroacridine-1,8-diones by three-component condensation of aromatic aldehydes with...     

Module assembly for protein-surface recognition: geranylgeranyltransferase I bivalent inhibitors for simultaneous targeting of interior and exterior protein surfaces

Synthetic chemical probes designed to simultaneously targeting multiple sites of protein surfaces are of interest owing to their potential application as site specific modulators of protein-protein interactions. A new approach toward bivalent inhibitors of mammalian type I geranylgeranyltransferase (GGTase I) based on module assembly for simultaneous recognition of both interior and exterior protein surfaces is reported. The inhibitors synthesized in this study consist of two modules linked by an alkyl spacer; one is the tetrapeptide CVIL module for binding to the interior protein surface (active pocket) and the other is a 3,4,5-alkoxy substituted benzoyl motif that contains three aminoalkyl groups designed to bind to the negatively charged protein exterior surface near the active site. The compounds were screened by two distinct enzyme inhibition assays based on fluorescence spectroscopy and incorporation of a [(3)H]-labeled prenyl group onto a protein substrate. The bivalent inhibitors block GGTase I enzymatic activity with K(i) values in the submicromolar range and are approximately one order of magnitude and more than 150 times more effective than the tetrapeptide CVIL and the methyl benzoate derivatives, respectively. The bivalent compounds 6 and 8 were shown to be competitive inhibitors, suggesting that the CVIL module anchors the whole molecule to the GGTase I active site and delivers the other module to the targeting protein surface. Thus, our module-assembly approach resulted in simultaneous multiple-site recognition, and as a consequence, synergetic inhibition of GGTase I activity, thereby providing a new approach in designing protein-surface-directed inhibitors for targeting protein-protein interactions.